Optimal Randomization Designs for Large Multicenter Clinical Trials: From the National Institutes of Health Stroke Trials Network Funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke Experience.

From 2016 to 2021, the National Institutes of Health Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke initiated ten multicenter randomized controlled clinical trials. Optimal subject randomization designs are demanded with 4 critical properties: (1) protection of treatment assignment randomness, (2) achievement of the desired treatment allocation ratio, (3) balancing of baseline covariates, and (4) ease of implementation. For acute stroke trials, it is necessary to minimize the time between eligibility assessment and treatment initiation. This article reviews the randomization designs for 3 trials currently enrolling in Stroke Trials Network funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke, the SATURN (Statins in Intracerebral Hemorrhage Trial), the MOST (Multiarm Optimization of Stroke Thrombolysis Trial), and the FASTEST (Recombinant Factor VIIa for Hemorrhagic Stroke Trial). Randomization methods utilized in these trials include minimal sufficient balance, block urn design, big stick design, and step-forward randomization. Their advantages and limitations are reviewed and compared with traditional stratified permuted block design and minimization.

Selection of a statistical analysis method for the Glasgow Outcome Scale-Extended endpoint for estimating the probability of favorable outcome in future severe TBI clinical trials.

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.

Designing a phase-III time-to-event clinical trial using a modified sample size formula and Poisson-Gamma model for subject accrual that accounts for the lag in site initiation using the PERT distribution.

A priori estimation of sample size and subject accrual in multi-site, time-to-event clinical trials is often challenging. Such trials are powered based on the number of events needed to detect a clinically significant difference. Sample size based on number of events relates to the expected duration of observation time for each subject. Temporal patterns in site initiation and subject enrollment ultimately affect when subjects can be accrued into the study. Lag times are common as the site start-up process optimizes, resulting in delays that may curtail observational follow-up and therefore undermine power. The proposed method introduces a Program Evaluation and Review Technique (PERT) model into the sample size estimation which accounts for the lag in site start-up. Additionally, a PERT model is introduced into a Poisson-Gamma subject accrual model to predict the quantity of study sites needed. The introduction of the PERT model provides greater flexibility in both a priori power assessment and planning the number of sites, as it specifically allows for the inclusion of anticipated delays in site start-up time. This model results in minimal power loss even when PERT distribution inputs are misspecified compared to the traditional assumption of simultaneous start-up for all sites. Together these updated formulations for sample size and subject accrual models offer an improved method for designing a multi-site time-to-event clinical trial that accounts for a flexible site start-up process.

Effect of Cilostazol in Animal Models of Cerebral Ischemia and Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.

BACKGROUND: Cilostazol, a phosphodiesterase III inhibitor, appears to be a promising agent for preventing cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage. Here, the authors perform a systematic review and meta-analysis to quantitatively assess the effects of cilostazol on brain structural and functional outcomes in animal models of cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm. METHODS: By using the PRISMA guidelines, a search of the PubMed, Scopus, and Web of Science was conducted to identify relevant studies. Study quality of each included study for both systematic reviews were scored by using an adapted 15-item checklist from the Collaborative Approach to Meta-Analysis of Animal Data from Experimental Studies. We calculated a standardized mean difference as effect size for each comparison. For each outcome, comparisons were combined by using random-effects modeling to account for heterogeneity, with a restricted maximum likelihood estimate of between-study variance. RESULTS: A total of 22 (median [Q1, Q3] quality score of 7 [5, 8]) and 6 (median [Q1, Q3] quality score of 6 [6, 6]) studies were identified for cerebral ischemia and subarachnoid hemorrhage-induced cerebral vasospasm, respectively. Cilostazol significantly reduced the infarct volume in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.88 (95% confidence interval [CI] [- 1.07 to - 0.70], p < 0.0001). Cilostazol significantly reduced neurofunctional deficits in cerebral ischemia models with a pooled standardized mean difference estimate of - 0.66 (95% CI [- 1.06 to - 0.28], p < 0.0001). Cilostazol significantly improved the basilar artery diameter in subarachnoid hemorrhage-induced cerebral vasospasm with a pooled standardized mean difference estimate of 2.30 (95% CI [0.94 to 3.67], p = 0.001). Cilostazol also significantly improved the basilar artery cross-section area with a pooled standardized mean estimate of 1.88 (95% CI [0.33 to 3.43], p < 0.05). Overall, there was between-study heterogeneity and asymmetry in the funnel plot observed in all comparisons. CONCLUSIONS: Published animal data support the overall efficacy of cilostazol in reducing infarct volume and neurofunctional deficits in cerebral ischemia models and cerebral vasospasm in subarachnoid hemorrhage models.

Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. METHODS: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL-<180 and ≥180 mg/dL, respectively, measured at baseline, 24, 48, and 72 hours. Persistent hyperglycemia was defined by 2 consecutive (24 hours apart) serum glucose levels. We evaluated the relationship between moderate and severe hyperglycemia and death or disability (defined by modified Rankin Scale score of 4-6) at 90 days in the overall cohort and in groups defined by preexisting diabetes. RESULTS: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1-2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2-2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P=0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0-3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1-3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. CONCLUSIONS: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.

Early Hyperchloremia is Independently Associated with Death or Disability in Patients with Intracerebral Hemorrhage.

BACKGROUND: On the basis of increased mortality associated with hyperchloremia among critically ill patients, we investigated the effect of occurrence of early hyperchloremia on death or disability at 90 days in patients with intracerebral hemorrhage (ICH). METHODS: We analyzed the data from Antihypertensive Treatment of Cerebral Hemorrhage 2 trial, which recruited patients with spontaneous ICH within 4.5 h of symptom onset. Patients with increased serum chloride levels (110 mmol/L or greater) at either baseline or 24, 48, or 72 h after randomization were identified. We further graded hyperchloremia into one occurrence or two or more occurrences within the first 72 h. Two logistic regression analyses were performed to determine the effects of hyperchloremia on (1) death within 90 days and (2) death or disability at 90 days after adjustment for potential confounders. RESULTS: Among the total of 1,000 patients analyzed, hyperchloremia within 72 h was seen in 114 patients with one occurrence and in 154 patients with two or more occurrences. Patients with one occurrence of hyperchloremia (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-5.5) and those with two or more occurrences (OR 2.6, 95% CI 1.3-5.0) had significantly higher odds of death within 90 days after adjustment for age, race and ethnicity, National Institutes of Health Stroke Scale score strata, hematoma volume, presence or absence of intraventricular hemorrhage, cigarette smoking, previous stroke, and maximum hourly dose of nicardipine. Patients with two or more occurrences of hyperchloremia (OR 3.4, 95% CI 2.1-5.6) had significantly higher odds of death or disability at 90 days compared with patients without hyperchloremia after adjustment for the abovementioned potential confounders. CONCLUSIONS: The independent association between hyperchloremia and death or disability at 90 days suggests that avoidance of hyperchloremia may reduce the observed death or disability in patients with ICH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01176565.

Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Intensive Blood Pressure Lowering and DWI Lesions in Intracerebral Hemorrhage: Exploratory Analysis of the ATACH-2 Randomized Trial.

BACKGROUND: With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. METHODS: We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110-139 mm Hg versus 140-179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. RESULTS: Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00-5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71-1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. CONCLUSIONS: Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials.

BACKGROUND: Monitoring and reporting of drug safety during a clinical trial is essential to its success. More recent attention to drug safety has encouraged statistical methods development for monitoring and detecting potential safety signals. This paper investigates the potential impact of the process of the blinded investigator identifying a potential safety signal, which should be further investigated by the Data and Safety Monitoring Board with an unblinded safety data analysis. METHODS: In this paper, two-stage Bayesian hierarchical models are proposed for safety signal detection following a pre-specified set of interim analyses that are applied to efficacy. At stage 1, a hierarchical blinded model uses blinded safety data to detect a potential safety signal and at stage 2, a hierarchical logistic model is applied to confirm the signal with unblinded safety data. RESULTS: Any interim safety monitoring analysis is usually scheduled via negotiation between the trial sponsor and the Data and Safety Monitoring Board. The proposed safety monitoring process starts once 53 subjects have been enrolled into an eight-arm phase II clinical trial for the first interim analysis. Operating characteristics describing the performance of this proposed workflow are investigated using simulations based on the different scenarios. CONCLUSIONS: The two-stage Bayesian safety procedure in this paper provides a statistical view to monitor safety during the clinical trials. The proposed two-stage monitoring model has an excellent accuracy of detecting and flagging a potential safety signal at stage 1, and with the most important feature that further action at stage 2 could confirm the safety issue.

Correction to: Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials.

An amendment to this paper has been published and can be accessed via the original article.

Worldwide Organization of Neurocritical Care: Results from the PRINCE Study Part 1.

INTRODUCTION: Neurocritical care focuses on the care of critically ill patients with an acute neurologic disorder and has grown significantly in the past few years. However, there is a lack of data that describe the scope of practice of neurointensivists and epidemiological data on the types of patients and treatments used in neurocritical care units worldwide. To address these issues, we designed a multicenter, international, point-prevalence, cross-sectional, prospective, observational, non-interventional study in the setting of neurocritical care (PRINCE Study). METHODS: In this manuscript, we analyzed data from the initial phase of the study that included registration, hospital, and intensive care unit (ICU) organizations. We present here descriptive statistics to summarize data from the registration case report form. We performed the Kruskal-Wallis test followed by the Dunn procedure to test for differences in practices among world regions. RESULTS: We analyzed information submitted by 257 participating sites from 47 countries. The majority of those sites, 119 (46.3%), were in North America, 44 (17.2%) in Europe, 34 (13.3%) in Asia, 9 (3.5%) in the Middle East, 34 (13.3%) in Latin America, and 14 (5.5%) in Oceania. Most ICUs are from academic institutions (73.4%) located in large urban centers (44% > 1 million inhabitants). We found significant differences in hospital and ICU organization, resource allocation, and use of patient management protocols. The highest nursing/patient ratio was in Oceania (100% 1:1). Dedicated Advanced Practiced Providers are mostly present in North America (73.7%) and are uncommon in Oceania (7.7%) and the Middle East (0%). The presence of dedicated respiratory therapist is common in North America (85%), Middle East (85%), and Latin America (84%) but less common in Europe (26%) and Oceania (7.7%). The presence of dedicated pharmacist is highest in North America (89%) and Oceania (85%) and least common in Latin America (38%). The majority of respondents reported having a dedicated neuro-ICU (67% overall; highest in North America: 82%; and lowest in Oceania: 14%). CONCLUSION: The PRINCE Study results suggest that there is significant variability in the delivery of neurocritical care. The study also shows it is feasible to undertake international collaborations to gather global data about the practice of neurocritical care.

Global Survey of Outcomes of Neurocritical Care Patients: Analysis of the PRINCE Study Part 2.

BACKGROUND: Neurocritical care is devoted to the care of critically ill patients with acute neurological or neurosurgical emergencies. There is limited information regarding epidemiological data, disease characteristics, variability of clinical care, and in-hospital mortality of neurocritically ill patients worldwide. We addressed these issues in the Point PRevalence In Neurocritical CarE (PRINCE) study, a prospective, cross-sectional, observational study. METHODS: We recruited patients from various intensive care units (ICUs) admitted on a pre-specified date, and the investigators recorded specific clinical care activities they performed on the subjects during their first 7 days of admission or discharge (whichever came first) from their ICUs and at hospital discharge. In this manuscript, we analyzed the final data set of the study that included patient admission characteristics, disease type and severity, ICU resources, ICU and hospital length of stay, and in-hospital mortality. We present descriptive statistics to summarize data from the case report form. We tested differences between geographically grouped data using parametric and nonparametric testing as appropriate. We used a multivariable logistic regression model to evaluate factors associated with in-hospital mortality. RESULTS: We analyzed data from 1545 patients admitted to 147 participating sites from 31 countries of which most were from North America (69%, N = 1063). Globally, there was variability in patient characteristics, admission diagnosis, ICU treatment team and resource allocation, and in-hospital mortality. Seventy-three percent of the participating centers were academic, and the most common admitting diagnosis was subarachnoid hemorrhage (13%). The majority of patients were male (59%), a half of whom had at least two comorbidities, and median Glasgow Coma Scale (GCS) of 13. Factors associated with in-hospital mortality included age (OR 1.03; 95% CI, 1.02 to 1.04); lower GCS (OR 1.20; 95% CI, 1.14 to 1.16 for every point reduction in GCS); pupillary reactivity (OR 1.8; 95% CI, 1.09 to 3.23 for bilateral unreactive pupils); admission source (emergency room versus direct admission [OR 2.2; 95% CI, 1.3 to 3.75]; admission from a general ward versus direct admission [OR 5.85; 95% CI, 2.75 to 12.45; and admission from another ICU versus direct admission [OR 3.34; 95% CI, 1.27 to 8.8]); and the absence of a dedicated neurocritical care unit (NCCU) (OR 1.7; 95% CI, 1.04 to 2.47). CONCLUSION: PRINCE is the first study to evaluate care patterns of neurocritical patients worldwide. The data suggest that there is a wide variability in clinical care resources and patient characteristics. Neurological severity of illness and the absence of a dedicated NCCU are independent predictors of in-patient mortality.

Relationship Between Vascular Risk Factors and Location of Intracranial Atherosclerosis in the SAMMPRIS Trial.

BACKGROUND: Previous studies have reported that different locations of intracranial atherosclerosis (ICAS) are associated with different demographic features and vascular risk factors. We aimed to examine this observation in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial population. METHODS: SAMMPRIS was a randomized controlled trial that enrolled 451 patients with recent transient ischemic attack or stroke-related due to severe (70%-99%) stenosis of a major intracranial artery. We compared the baseline demographic features and vascular risk factors between the symptomatic artery locations. Wilcoxon test was used to compare continuous variables, and chi-square test was used for categorical variables. RESULTS: Of 449 patients included in the analysis; 289 (64.4%) had ICAS in the anterior circulation and 160 (35.6%) in the posterior circulation. Features that were significantly different between patients with anterior versus posterior ICAS were: median age (58.3 years versus 64.0 years, P < .001), males/females (52.9%/47.1% versus 74.4%/25.6% P < .001), white/black (66.8%/26.6% versus 79.4%/16.9%, P = .02), and history of hyperlipidemia (85.5% versus 92.5%, P = .03). CONCLUSIONS: The observed differences in the distribution of demographic characteristics and vascular risk factors depending on the location of symptomatic ICAS suggest the possibility of different underlying pathological processes involved in the formation of atherosclerotic plaques in different locations.

Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example.

Plasma Neutrophil Gelatinase-Associated Lipocalin Is Associated With Acute Kidney Injury and Clinical Outcomes in Neonates Undergoing Cardiopulmonary Bypass.

OBJECTIVES: Acute kidney injury is a frequent complication following neonatal cardiac surgery and is associated with significant morbidity and mortality. The objectives of this study were to determine if plasma neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury and clinical outcomes in neonates with congenital heart disease undergoing cardiopulmonary bypass. DESIGN: Retrospective single-center observational study. SETTING: A pediatric cardiac ICU within a tertiary-care academic hospital. PATIENTS: Patients age less than 30 days undergoing cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma neutrophil gelatinase-associated lipocalin peaked at 12 hours postcardiopulmonary bypass and more than doubled compared with preoperative levels. Higher preoperative and 24-hour postoperative neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury (r = 0.30, r = 0.49), longer duration of mechanical ventilation (r = 0.40, r = 0.51), ICU (r = 0.32, r = 0.33) and hospital lengths of stay (r = 0.28, r = 0.32), and total hospital charges (r = 0.35, r = 0.30; all p values < 0.05). CONCLUSIONS: Both preoperative and 24-hour postoperative plasma neutrophil gelatinase-associated lipocalin levels are associated with acute kidney injury and worse clinical outcomes in neonates undergoing cardiac surgery. Plasma neutrophil gelatinase-associated lipocalin levels may have a role in risk stratification for predicting postoperative renal dysfunction as well as providing a potential clinical trajectory in the postoperative period.

Treatment effect on ordinal functional outcome using piecewise multistate Markov model with unobservable baseline: an application to the modified Rankin scale.

In clinical trials, longitudinally assessed ordinal outcomes are commonly dichotomized and only the final measure is used for primary analysis, partly for ease of clinical interpretation. Dichotomization of the ordinal scale and failure to utilize the repeated measures can reduce statistical power. Additionally, in certain emergent settings, the same measure cannot be assessed at baseline prior to treatment. For such a data set, a piecewise-constant multistate Markov model that incorporates a latent model for the unobserved baseline measure is proposed. These models can be useful in analyzing disease history data and are advantageous in clinical applications where a disease process naturally moves through increasing stages of severity. Two examples are provided using acute stroke clinical trials data. Conclusions drawn in this article are consistent with those from the primary analysis for treatment effect in both of the motivating examples. Use of these models allows for a more refined examination of treatment effect and describes the movement between health states from baseline to follow-up visits which may provide more clinical insight into the treatment effect.

Common Data Element for Unruptured Intracranial Aneurysm and Subarachnoid Hemorrhage: Recommendations from Assessments and Clinical Examination Workgroup/Subcommittee.

BACKGROUND: Clinical studies of subarachnoid hemorrhage (SAH) and unruptured cerebral aneurysms lack uniformity in terms of variables used for assessments and clinical examination of patients which has led to difficulty in comparing studies and performing meta-analyses. The overall goal of the National Institute of Health/National Institute of Neurological Disorders and Stroke Unruptured Intracranial Aneurysms (UIA) and subarachnoid hemorrhage (SAH) Common Data Elements (CDE) Project was to provide common definitions and terminology for future unruptured intracranial aneurysm and SAH research. METHODS: This paper summarizes the recommendations of the subcommittee on SAH Assessments and Clinical Examination. The subcommittee consisted of an international and multidisciplinary panel of experts in UIA and SAH. Consensus recommendations were developed by reviewing previously published CDEs for other neurological diseases including traumatic brain injury, epilepsy and stroke, and the SAH literature. Recommendations for CDEs were classified by priority into "core," "supplemental-highly recommended," "supplemental" and "exploratory." RESULTS: We identified 248 variables for Assessments and Clinical Examination. Only the World Federation of Neurological Societies grading scale was classified as "Core." The Glasgow Coma Scale was classified as "Supplemental-Highly Recommended." All other Assessments and Clinical Examination variables were categorized as "Supplemental." CONCLUSION: The recommended Assessments and Clinical Examination variables have been collated from a large number of potentially useful scales, history, clinical presentation, laboratory, and other tests. We hope that adherence to these recommendations will facilitate the comparison of results across studies and meta-analyses of individual patient data.

Determining the joint effect of obesity and diabetes on functional disability at 3-months and on all-cause mortality at 1-year following an ischemic stroke.

BACKGROUND: Obesity and diabetes mellitus, or diabetes, are independently associated with post-ischemic stroke outcomes (e.g., functional disability and all-cause mortality). Although obesity and diabetes are also associated with post-ischemic stroke outcomes, the joint effect of obesity and diabetes on these post-ischemic stroke outcomes has not been explored previously. The purpose of the current study was to explore whether the effect of obesity on post-ischemic stroke outcomes differed by diabetes status in a cohort of acute ischemic stroke subjects with at least a moderate stroke severity. METHODS: Data from the Interventional Management of Stroke (IMS) III clinical trial was analyzed for this post-hoc analysis. A total of 656 subjects were enrolled in IMS III and were followed for one year. The joint effects of obesity and diabetes on functional disability at 3-months and all-cause mortality at 1-year were examined. RESULTS: Of 645 subjects with complete obesity and diabetes information, few were obese (25.74%) or had diabetes (22.64%). Obese subjects with diabetes and non-obese subjects without diabetes had similar odds of functional disability at 3-months following an ischemic stroke (adjusted common odds ratio, 1.038, 95% CI: 0.631, 1.706). For all-cause mortality at 1-year following an ischemic stroke, obese subjects with diabetes had a similar hazard compared with non-obese subjects without diabetes (adjusted hazard ratio, 1.005, 95% CI: 0.559, 1.808). There was insufficient evidence to declare a joint effect between obesity and diabetes on either the multiplicative scale or the additive scale for both outcomes. CONCLUSIONS: In this post-hoc analysis of data from the IMS III clinical trial of acute ischemic stroke patients with at least a moderate stroke severity, there was not sufficient evidence to determine that the effect of obesity differed by diabetes status on post-ischemic stroke outcomes. Additionally, there was not sufficient evidence to determine that either factor was independently associated with all-cause mortality. Future studies could differentiate between metabolically healthy and metabolically unhealthy patients within BMI categories to determine if the effect of obesity on post-stroke outcomes differs by diabetes status.

Human Albumin Use in Adults in U.S. Academic Medical Centers.

OBJECTIVE: To determine rates and predictors of albumin administration, and estimated costs in hospitalized adults in the United States. DESIGN: Cohort study of adult patients from the University HealthSystem Consortium database from 2009 to 2013. SETTING: One hundred twenty academic medical centers and 299 affiliated hospitals. PATIENTS: A total of 12,366,264 hospitalization records. INTERVENTIONS: Analysis of rates and predictors of albumin administration, and estimated costs. MEASUREMENTS AND MAIN RESULTS: Overall the proportion of admissions during which albumin was administered increased from 6.2% in 2009 to 7.5% in 2013; absolute difference 1.3% (95% CI, 1.30-1.40%; p < 0.0001). The increase was greater in surgical patients from 11.7% in 2009 to 15.1% in 2013; absolute difference 3.4% (95% CI, 3.26-3.46%; p < 0.0001). Albumin use varied geographically being lowest with no increase in hospitals in the North Eastern United States (4.9% in 2009 and 5.3% in 2013) and was more common in bigger (> 750 beds; 5.2% in 2009 and 7.3% in 2013) compared to smaller hospitals (< 250 beds; 4.4% in 2009 to 6.2% in 2013). Factors independently associated with albumin use were appropriate indication for albumin use (odds ratio, 65.220; 95% CI, 62.459-68.103); surgical admission (odds ratio, 7.942; 95% CI, 7.889-7.995); and high severity of illness (odds ratio, 8.933; 95% CI, 8.825-9.042). Total estimated albumin cost significantly increased from $325 million in 2009 to $468 million in 2013; (absolute increase of $233 million), p value less than 0.0001. CONCLUSIONS: The proportion of hospitalized adults in the United States receiving albumin has increased, with marked, and currently unexplained, geographic variability and variability by hospital size.

ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data From Parts 1 and 2.

BACKGROUND AND PURPOSE: The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. METHODS: The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). RESULTS: The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87-15.57). CONCLUSIONS: Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00235495.